Drugs of abuse cause persistent changes in brain function, leading to long lasting changes in behavior that are extremely resistant to extinction (an experience-dependent process by which a previously learned behavior is reduced). A common finding from studies of drug abuse is that exposure to the context in which drug use occurs elicits memories and behaviors that result in relapse to drug-seeking behavior and subsequent drug use. Accumulating evidence shows that these persistent changes in brain function are mediated by altered gene transcription. Recently, it has become clear that regulation of gene transcription necessary for drug- associated memories involves the concerted action of multiple transcription factors and cofactors that interact with chromatin, a protein complex that packages DNA. Chromatin modification via histone acetylation (a form of epigenetic gene regulation) is emerging as a major molecular pathway involved in regulation of gene expression required for long-term memory as well as substance abuse. However, the role of the specific histone modifying enzymes involved in the acquisition and extinction of drug-induced memories remains unknown. The primary goal of this proposal incorporates behavioral, pharmacological, and molecular approaches to examine the role of histone acetylating/deacetylating enzymes that may underlie the formation and extinction of drug-induced memories. The first aim of this research proposal is to determine the ability of histone deacetylase inhibition, which relaxes chromatin structure and thereby enhances gene transcription, to enhance the rate and persistence of extinction of drug-associated memories. Epigenetic gene regulation has been shown to underlie persistent long-term changes at the cellular level as well as the behavioral level, which raises the possibility that histone deacetylase inhibition may generate a form of extinction that is refractive to reinstatement of drug-seeking behavior. The second aim will examine the role of CREB-binding protein (CBP), a histone acetyltransferase and transcriptional coactivator, in the acquisition of drug-associated memories. The focus of the third aim is to examine the role of CBP in the extinction of drug-associated memories. In both the second and third aims, I will be using novel genetic techniques to generate site specific deletions of the Cbp gene in the nucleus accumbens. My research plan focuses on epigenetic mechanisms underlying the formation and extinction of drug-associated memories. By understanding the epigenetic mechanisms involved in the formation and extinction of drug-associated memories, we can identify a potential therapeutic approach for the treatment of cocaine addiction. The translational value of these findings has the potential to greatly impact the number of people who complete a treatment program. Further, HDAC inhibitors are FDA approved drugs, which significantly increases the potential translational value of this research. PUBLIC HEALTH RELEVANCE: Cocaine addiction is a major public health problem in the United States. By understanding the epigenetic mechanisms involved in the formation and extinction of drug-associated memories, we can identify a potential therapeutic approach for the treatment of cocaine addiction.